Risk of progression from Barrett's oesophagus to cancer

Treating all patients with Barrett's oesophagus is currently unfeasible as it occurs in at least 0.5% of the UK population (and is not supported by number‐needed‐to‐treat analyses) (Cameron 1990). Progression from non‐dysplastic Barrett's oesophagus to malignancy is rare. Large studies from Northern Ireland and Denmark suggest a malignant progression rate of 0.12% to 0.39% of patients per year (Bhat 2011; Hvid‐Jensen 2011; Yousef 2008), although these may be underestimates as the studies defined Barrett's histologically rather than endoscopically and are therefore likely to have included a number of patients without true Barrett's. The most common type of metaplastic epithelium, specialised intestinal metaplasia (intestinalisation), is considered to have a major potential to develop into adenocarcinoma. Some studies have suggested that genetic changes play a key role in this progression to cancer. Adenocarcinoma can develop in Barrett's oesophagus with these genetic changes even in the absence of intestinalisation (Kelty 2007; Liu 2009). It is hoped that research in progress will identify appropriate strategies for risk assessment, treatment and surveillance in this population (Konda 2012).

There is marked variation in the reported malignant potential of LGD. Skacel 2000 followed 25 patients with LGD for 26 months and found that 8% had persistent LGD, 60% regressed and 28% went on to develop HGD or adenocarcinoma (4% were indefinite for dysplasia at follow‐up). Sharma 2006 followed 156 patients with LGD for a mean of 4.1 years and reported stable LGD in 21%, regression in 66% and progression to HGD or cancer in 13%. These data support an earlier audit of a Barrett's epithelium surveillance database, where one in 10 cases of LGD progressed to cancer over an observation period of five years (Basu 2004). However, other studies have shown progression rates below 5% (Wani 2009). In one prospective cohort study of 713 patients with Barrett's oesophagus, including 111 with LGD, which reported that, compared to non‐dysplastic disease, LGD was a significant risk factor for progression to HGD or adenocarcinoma (risk ratio (RR) 9.7; 95% confidence interval (CI) 4.4 to 21.5) (Sikkema 2010).

This variation in the reported malignant potential of LGD partly reflects difficulties in establishing an accurate histological diagnosis. It has been demonstrated that non‐dysplastic Barrett's oesophagus is frequently over‐diagnosed as LGD by non‐specialist pathologists (Curvers 2010). The study authors concluded that the true significance of LGD may be underestimated by the majority of studies that have relied on single pathologist reporting.

In this review, we chose not to address LGD in Barrett's oesophagus. We included both HGD and IMC (mucosal neoplasia) in this review, owing to the suboptimal techniques available to differentiate between them. In addition, their biological behaviour is similar, as both have a low risk of nodal spread.

Literature suggests that, in those with biopsy‐confirmed HGD, the rate of submucosally invasive cancer is 12.7% in those with endoscopically visible HGD and 3% for those with no detectable lesion (Konda 2008). There is variability in the reported risk of lymph node metastases in patients with intramucosal and submucosal (T1) oesophageal adenocarcinoma, which may be accounted for by differences in depth of invasion, size, presence of lympho‐vascular invasion and tumour grade. One retrospective review of 126 T1a and T1b tumours reported that although lymph node metastases were rare (1.3%) with intramucosal tumours, submucosal invasion of any extent carried a significant risk of lymph node metastases (and is thus unsuitable for endoscopic treatment) (Leers 2011). This has not been the experience of others who have concluded that superficial submucosal invasion is low risk for metastases (Alvarez Herrero 2010). Careful histopathology of ER specimens should influence the decision whether to treat endoscopically or by oesophagectomy (Peters 2008). Mortality rates for oesophagectomy may exceed 2%, hence a small risk of lymph node metastases may be acceptable after endoscopic therapy.

Surgery or endotherapy?

If visible lesions suspicious of dysplasia are found in the setting of Barrett's oesophagus, ER should be performed in order to obtain an accurate histological diagnosis. A variety of options including resection or ablative therapies, followed by adequate surveillance, are available to treat the epithelium.

Surgical therapies, although effective, are costly and carry appreciable patient mortality and morbidity. Ablative endotherapies allow restoration of the normal squamous lining and thereby remove both existing dysplasia and the potential for development of dysplasia (Sampliner 1996). In patients with HGD, endotherapies may offer an alternative to oesophagectomy with comparable survival, lower mortality and morbidity (Pacifico 2003, Schembre 2008), and less disruption of QoL (Rosmolen 2010; Schembre 2010), especially since patients with Barrett's oesophagus have considerable co‐morbidity (Moayyedi 2008).

Post‐oesophagectomy mortality and morbidity are important issues; DeMeester 2008 suggested that quoted high postoperative mortality rates were not supported by more recent studies of patients with HGD or early cancer who were treated by oesophagectomy, although there is a volume to performance relationship (Chang 2006). In one retrospective case series, vagal‐sparing oesophagectomy was associated with less peri‐operative morbidity, a shorter hospital stay and fewer late complications such as weight loss, diarrhoea and dumping, than other surgical techniques (Peyre 2007). In that study, postoperative mortality was similar for all types of surgical resection (30‐day mortality percentage; vagal‐sparing 2%, transhiatal 5%; en‐bloc 0%) and survival was reported to be excellent (percentage survival over 60 months, in 85 patients diagnosed with cancer, all‐cause mortality: vagal sparing 89%; transhiatal 65%; en bloc 95%). While oesophagectomy can potentially offer the chance of complete resection of diseased tissue in patients with HGD or early (intramucosal) adenocarcinoma, recurrent Barrett's metaplasia or neoplasia may still appear after resection with curative intent (Wolfson 2004).

While different surgical techniques used for oesophagectomy offer broadly similar results, the endotherapy arm of many of the reports reviewed here were found to be much more heterogeneous. Published studies do consistently report endoscopic therapy to be safe and effective. For example in Shaheen 2009, a multicentre, sham‐controlled randomised trial, participants received either RFA or a sham procedure. In patients with dysplastic Barrett's oesophagus, RFA was associated with a high rate of complete eradication of both dysplasia and intestinal metaplasia and a reduced risk of disease progression, and few serious adverse effects. Medium‐term follow‐up data have demonstrated that these effects are durable at three years (Shaheen 2011).

While we found no RCTs that directly compared the results of surgery versus endotherapies, Attwood 2003 followed 29 patients with Barrett's‐related HGD who were deemed unfit for or declined surgery, instead undergoing argon beam photocoagulation. He showed that survival over seven years was not different to the general age‐ and sex‐matched population. This would suggest that, in those patients unable or unwilling to undergo oesophagectomy, endoscopic therapy offers a significant survival benefit over no therapy at all. Greenstein 2008 used the Surveillance, Epidemiology, and End Results (SEER) cancer registry data to compare survival in patients having either endoscopic therapy or no therapy. There was a significantly better oesophageal cancer‐related survival in the endoscopically treated group. It cannot be assumed that all of this group were deemed unfit for surgery, but non‐cancer‐related survival curves were similar between the groups suggesting similar co‐morbidities.

Schembre 2008 concluded that "both endotherapy and esophagectomy can effectively treat high‐grade dysplasia and intramucosal carcinoma associated with Barrett's esophagus". Endotherapy is associated with a higher risk of tumor progression, although this is uncommon. Esophagectomy incurs higher initial costs and results in more frequent minor complications but is usually curative. In this study, exclusion of the 'unfit for surgery' participants resulted in only 3% developing cancer (5% HGD) at the latest follow up (with no major complications and 27% minor complications), significantly fewer compared with the surgical group. One retrospective matched cohort comparison of oesophagectomy versus ER and APC in IMC reported effective treatment outcomes for both strategies after four years of follow‐up (Pech 2011). Complete remission of Barrett's was achieved in all patients in the surgical group and 98.7% in the ER group. 90 day mortality was 2.6% following surgery and 0% following endotherapy and major complications were only observed in the surgical group (32%). No tumour‐related mortality was observed in either group demonstrating that both strategies provided effective treatment in the medium term.

Adverse effects and treatment failure

Complications may arise as a result of endotherapy and there is the possibility of treatment failure as local endoscopic therapies can leave much of the oesophagus intact and often untreated.

A review of 12 publications on ER for early Barrett's neoplasia (Pech 2007) showed recurrence rates of 0% to 21%, minor complications in 0% to 46% and few major complications. Ell 2007 published single centre results of ER in 100 consecutive patients with early Barrett's adenocarcinoma (total 144 resections) showing no major complications, 11 minor complications (all bleeds without decrease in haemoglobin (Hb) > 2 g/dL) and local remission in 99% of patients after 1.9 months with a five‐year survival rate of 98% (both of the patient deaths were from unrelated causes).

One retrospective matched cohort comparison of oesophagectomy versus ER and APC in T1 cancer reported cancer‐free remission for both strategies after four years of follow‐up (Pech 2011). Complete remission of Barrett's was achieved in all patients in the surgical group and 98.7% in the ER group. Ninety‐day mortality was 2.6% following surgery and 0% following endotherapy and major complications were only observed in the surgical group (32%). No tumour‐related mortality was observed in either group demonstrating that both strategies provided effective treatment in the medium term.

When focused local therapy is used to remove an HGD/early cancer lesion within a Barrett's segment, there often remains a significant amount of residual Barrett's. After endotherapy, the remaining Barrett's has a high malignant potential and small patches of early dysplasia can easily be missed at initial treatments. In patients who have already developed an area of HGD/early cancer, it is likely that the residual Barrett's has a greater malignant potential (field change effect) than in those who have never developed a dysplastic lesion. Many studies have therefore used a combination of local therapies, for example EMR to remove the HGD/early cancer lesions and wide‐field ablation modalities (most commonly PDT or RFA) to treat the residual Barrett's in an attempt to reduce the rate of metachronous lesions found at follow‐up.

One randomised study of HGD in Barrett's by Overholt 2007 compared PDT plus omeprazole to omeprazole alone and demonstrated that at five years those in the PDT group were less likely to have detectable HGD (77% versus 39%) or cancer (29% versus 15%). Photosensitivity reactions and oesophageal strictures were reported as adverse events, but no long‐term effects of oesophageal strictures or photosensitivity reactions were seen by the end of the study. There is some concern that PDT may simply 'bury' the pre‐malignant tissue under neo‐squamous epithelium (Mino‐Kenudson 2007), although these areas seem to have a low malignant potential (Biddlestone 1998; Hornick 2007) and may simply atrophy over time (Hornick 2005). PDT also has a relatively high rate of complications (e.g. strictures and photosensitisation). One retrospective review of 50 patients treated by PDT for HGD or early oesophageal cancer showed there was no procedure‐related mortality, but 42% of the patients developed oesophageal stricture (Keeley 2007). Bronner 2009 reported that squamous overgrowth following PDT did not obscure the most advanced neoplasia in any patient.

Recurrence or metachronous lesions occur relatively frequently but repeat local therapy is usually possible and successful. Schnell 2001 demonstrated that the risk of cancer developing from HGD after the first year was 16% in a group of 75 people followed up for a mean of seven years (managing these patients with a strategy of frequent endoscopic surveillance with biopsies). May 2002 showed that in a group of 115 patients with dysplastic areas, most of whom had early cancer (96 early cancer, 19 HGD), 30% developed a metachronous cancer after undergoing local therapy, usually EMR alone (EMR alone in 70, PDT alone in 32, EMR and PDT in 10 and APC alone in three) over a mean follow‐up period of 34 months. A study by Pech 2006 including 304 patients undergoing ER, PDT, or both, followed for a mean of 69.5 months reported tumour‐related deaths in two inoperable patients. Complications in this study included bleeding in 11% and stricture formation in 3.3%, all of which were managed endoscopically. Pech 2008 reported long‐term results from a cohort of patients with Barrett's neoplasia, who were treated endoscopically. Three hundred and forty‐nine patients were followed up for a mean of 63.6 months. A complete response was seen in 96.6% and surgery was necessary in 3.7% after endoscopic therapy failed. Metachronous lesions developed during the follow‐up in 74 patients (21.5%); 56 died of concomitant disease, but none died of Barrett's neoplasia. The calculated five‐year survival rate was 84%. The reason for the high rate of recurrence seemed to be a result of the undetected neoplasia in the Barrett's segment after endoscopic therapy. Moss 2010, in Australia, demonstrated the effects of ER on histological grade and stage of adenocarcinoma, in a prospective study at two centres (N = 75) using ER for HGD or oesophageal adenocarcinoma, there was no recurrence at resected sites, 11% developed metachronous lesions and five developed submucosal invasion treated by oesophagectomy. There were no deaths due to adenocarcinoma. The study authors concluded that ER altered histological grade or local T stage and resulted in reduced oesophagectomy rates.

There are promising results from using either circumferential ER (Giovannini 2004; Peters 2006) or RFA (Gondrie 2008a; Gondrie 2008b; Sharma 2008) to reduce the future malignant potential of the residual Barrett's safely. In terms of eradication of Barrett's oesophagus tissue, RFA seems to be able to remove benign Barrett's oesophagus completely without any major complications (Sharma 2007) but the results of further studies, ideally RCTs, are awaited (Rösch 2008; Sharma 2009; Singh 2009). After endotherapy, patients must continue to attend for surveillance endoscopies and of note 13% of the endotherapy group in Schembre 2008 failed to attend the follow‐up appointments upon which success may depend.

Quality of life

The assessment of QoL in clinical trials does not have a universally accepted definition, although Efficace 2003 suggested that a number of standard criteria could be employed. Ideally the measures should be multi‐dimensional and self‐reported (Blazeby 2007). Both treatment modalities appeared to have a similar impact on QoL one year or more after treatment compared with age‐matched controls and younger patients who had oesophagectomy had a greater impairment in QoL than older patients who had surgery (Schembre 2010). Prasad 2007 made some attempt to look at QoL retrospectively by noting the Eastern Cooperative Oncology Group performance scores (ECOG PS) pre‐treatment and at the end of follow‐up. The proportion of patients with an ECOG PS of one or less 1 (equivalent to being symptomatic but completely ambulatory or being asymptomatic) in the endoscopic therapy/surgical groups was similar before and after treatment.

Rosmolen 2010 explored QoL and fear of cancer recurrence in 81 patients over a follow‐up period of 12 to 60 months after endoscopic or surgical treatment for early Barrett's neoplasia using a non‐randomised cross‐sectional design. There were more eating problems and reflux symptoms in the surgery group but those treated endoscopically were reported to have more fear of recurrence surgery patients (statistically significant). The study investigators commented that strategies to educate and address fear of cancer recurrence may be useful. Future studies would ideally report on QoL as well as survival and incidence of recurrent or new dysplasia and cancer.

Cost

Schembre 2008 reported that hospital charges were USD40,079 in the endotherapy group as compared with USD66,060 in the surgical group over a mean follow‐up period of 20 and 48 months, respectively. However, the surgical group was unlikely to generate further costs whereas the endoscopic therapy group would require long‐term surveillance and possibly further treatments. A study by Hur 2003 showed that, for these reasons, PDT‐treated patients would generate higher costs than those undergoing oesophagectomy in the long term. A subsequent detailed cost‐effectiveness analysis was undertaken in Shaheen 2004 using decision analysis modelling to compare endoscopic surveillance, endoscopic ablation therapies and oesophagectomy in HGD in Barrett's oesophagus. They found endoscopic ablation therapy to be both cheaper and more effective (in terms of discounted quality‐adjusted life years) than oesophagectomy, even when the model was weighted towards oesophagectomy by assuming all surgery was undertaken in high volume centres and all endoscopic ablation patients required costly long‐term endoscopic surveillance post‐treatment. Endoscopic surveillance was the least expensive option but resulted in almost 20% of the patients developing cancer. Oesophagectomy provided the lowest risk of developing cancer but only when yearly rates of progression of HGD to cancer exceeded an unrealistic 30% did it become the most cost‐effective option. Vij 2004 used a similar decision analysis model to compare costs of PDT and oesophagectomy and concluded that PDT followed by endoscopic surveillance incurred greater life‐time cost but was more cost‐effective in terms of quality‐adjusted life years. In a hypothetical cohort of male patients with Barrett's oesophagus and HGD, PDT and oesophagectomy or surveillance were examined. Surveillance was the least costly approach, but the least effective. The report concluded that PDT and oesophagectomy were cost‐effective alternatives to surveillance only (Comay 2007). This is further supported by a decision analysis model by Pohl 2009. This mathematical modelling study concluded that although only limited long‐term outcomes of endotherapies are available, endoscopic therapy for early Barrett's oesophagus adenocarcinoma is more effective and costs less than surgical therapy.

A cost‐utility analysis using a decision analysis model based on a hypothetical cohort of 50‐year old patients with a diagnosis of Barrett's oesophagus, endoscopic ablation of HGD in subjects with Barrett's oesophagus was found to be "probably cost effective" in that it was estimated to be less costly and more effective than oesophagectomy or surveillance alone. Ablation of HGD was found to be capable of extending life expectancy by more than three quality‐adjusted life years at an incremental cost of less than USD6000 compared with no intervention. While the costs of different ablation types varied, they seem to be similar in terms of effectiveness. The authors noted that "as further post ablation data become available, the optimal strategy to be implemented will be clarified" (Inadomi 2009).

One UK‐based cost‐utility analysis of RFA or oesophagectomy concluded that a policy of RFA with oesophagectomy for HGD recurrence was a cost‐effective strategy when compared to immediate oesophagectomy (Boger 2010). RFA generated an additional 0.4 quality‐adjusted life years at a cost saving of GBP1902 compared to oesophagectomy. Boger 2010 concluded that only with an RFA failure rate (progression or persistence of HGD) of more than 44% or an annual risk of HGD recurrence of more than 15% following ablation would immediate oesophagectomy become the more cost‐effective option in the management of HGD. Similarly, one systematic review of the cost‐effectiveness of PDT in HGD identified three out of four studies where PDT ablation was found to be cost‐effective compared to oesophagectomy or endoscopic monitoring, although reported cost‐effectiveness ratios varied widely between each study (Sanchez 2010).